Emergence of chloroquine-resistant Plasmodium falciparum species is a major obstacle to the chemotherapy of malaria. In addition to the need for discovery of novel antimalarials, exploration of mechanism(s) of chloroquine resistance has become of paramount importance. Recently, patterns of chloroquine resistance in P. falciparum have been mapped to a 36 kb segment of chromosome 7 harboring a small cluster of genes, including Pfctr, a gene encoding an integral membrane protein with complex polymorphisms. Recently, we have discovered a novel agent, a 3-methoxy-substituted amine phenolate metal(III) complex (MR045), that selectively targets chloroquine-resistant clones associated with specific polymorphisms in this 36 kb segment. This lead compound inhibits the parasite heme polymerization reaction, the same putative target as chloroquine, but traverses the chloroquine resistance mechanism in all strains tested to date. In fact, the antimalarial activity of MR045 maps in perfect linkage with resistance polymorphisms in Pfctr, including the Sudan 106/1 strain, an exceptional case for other candidate genes in this segment. Furthermore, a close analogue now has been discovered, MR082, which shows the exact inverse activity. We propose to further explore structure-activity relationships by synthesis of additional analogues based on this reciprocal pair, identify candidate chloroquine resistance proteins by synthesis of photoaffinity analogues to probe cells and extracts, and localize the drug in cells in situ by incorporation of fluorophores into the motif for correlation with the location of candidate chloroquine resistance proteins. These versatile metal(III) complexes will also be radiolabeled and used in binding, transport and competitive biochemical assays with membrane preparations, digestive vacuoles, and purified PfCTR protein in relation to the chloroquine resistance phenotype. Therefore, these reagents provide unique tools to explore mechanism(s) of chloroquine resistance and provide promising leads for the generation of novel drug candidates that target chloroquine resistant organisms.